Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates

ABSTRACT

Methyl (R)-2-(R 1 OSO 2 )-2-(2-chlorophenyl)acetates useful as intermediates in the preparation of methyl (S)-2(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)acetate.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of prior application Ser. No.09/509,879, filed Oct. 6, 2000, now U.S. Pat. No. 6,573,381, which is a35 U.S.C. §371 application of PCT International application No.PCT/FR98/02082, filed Sep. 29, 1998.

The present invention concerns, in a general fashion, new derivatives ofhydroxyacetic esters, and their use as synthesis intermediates.

More specially, the object of the invention is the sulphonyloxyaceticesters with the general formula:

in which R₁ represents a benzyl group, a C₁-C₄ alkyl, which may besubstituted by one or several halogen atoms, such as chlorine orbromine, or a phenyl group, which may be substituted by one or severalhalogen atoms or by one or several linear or branched C₁-C₄ alkyl groupsor by a nitro group.

In particular, the invention concerns formula-I compounds in which R₁represents a methyl, ethyl, propyl, trifluoromethyl, benzyl, phenyl,chlorophenyl, tolyl, trimethylphenyl, triisopropylphenyl, dichlorophenylin particular 2,5-dichlorophenyl or nitrophenyl, in particularp-nitrophenyl, group.

Formula-I compounds have demonstrated themselves to be particularlyuseful as intermediates, notably for the synthesis of methyl(S)-2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno [3,2-c]-5-pyridyl)acetate or clopidrogel.

This enantiomer, which has the following structural formula:

is known for its therapeutic value, notably for its inhibition ofplatelet aggregation and antithrombotic properties.

In patent EP 0465358, a process is described for the preparation of the(R) and (S) enantiomers of2-(halogenophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl) acetateof a C₁-C₄ alkyl, using 2-arylacetic esters with a labile group in the 2position.

According to this process:

-   -   a) racemic a C₁-C₄ alkyl 2-(halogenophenyl)-2-halogeno or a        C₁-C₄ alkylsulphonyloxy, or C₆-C₁₀ alkyl arylsulphonyloxy)        acetate is coupled with 4,5,6,7-tetrahydrothieno [3,2-c]        pyridine in the form of a base or salt to obtain a racemic        compound.    -   b) the racemate thus formed is resolved by recrystallising        optically active acid salts to obtain the desired (R) or (S)        enantiomers.

However, the only example given of this process started from racemicmethyl 2(2-chlorophenyl)-2-chloroacetate for the final preparation ofclopidogrel and no precise indication or example was given to illustratethe preparation of a C₁-C₄ alkyl 2-(halophenyl)-2-(bromo oralkylsulfonyloxy or arylsulphonyloxy)-acetate

According to this example, clopidogrel is obtained by carrying out thefollowing 5 steps, starting from a 2-hydroxyacetic ester:

-   -   a) and b) reaction of racemic 2(2-chlorophenyl)-2-hydroxyacetic        acid with phosphorus pentachloride and esterification with        methanol to form racemic methyl        2-(2-chlorophenyl)-2-chloroacetate with a 45% yield,    -   c) coupling of the methyl 2-(2-chlorophenyl)-2-chloroacetate        formed in this way, with 4,5,6,7-tetrahydrothieno        [3,2-c]pyridine in the presence of potassium carbonate, which        yields racemic methyl 2-(4,5,6,7-tetrahydrothieno        [3,2-c]-5-pyridyl)-2(2-chlorophenyl)-acetate, with a mean yield        of 80%,    -   d) resolution of the racemate obtained by salification with        camphosulphonic acid (yield: 88% in terms of the salt desired)    -   e) regeneration of clopidogrel in basic form by treating the        camphosulphonic salt in question with sodium bicarbonate

Using this process, clopidogrel is obtained with a chemical yield of upto 30% from 2(2-chlorophenyl)-2-hydroxyacetic acid.

During the preliminary trials carried out in the context of the presentinvention, an attempt was made to prepare clopidogrel or its (R)enantiomer by means of an analogous reaction to that described in thepatent already referred to, but starting from the (R) or (S) enantiomerof methyl 2(2-chlorophenyl)-2-chloroacetate.

However, all the tests performed in methanol, acetonitrile or ethylacetate as solvent at a temperature between room temperature and 65° C.,with 1 or 2 equivalents of 4,5,6,7-tetrahydrothieno[3,2-c] pyridineeither in the form of the base or in the form of the hydrochloride, withor without sodium bicarbonate, led to the production of 72 to 88% ofracemic methyl 2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl) acetate

Other tests carried out with heating to 80° C. and using methyl(S)-2(2-chlorophenyl)-2-chloroacetate and 4,5,6,7-tetrahydrothieno[3,2-c] pyridine in the presence of sodium carbonate and in a solventmixture of methylisobutyl ketone/water yielded methyl(R)-2(4,5,6,7-tetrahydrothieno [3,2-c]-5-pyridyl)-2(chlorophenyl)acetate with an entantiomeric excess of only 20%.

Consequently, the development of a process for the preparation ofclopidogrel from 4,5,6,7-tetrahydrothieno [3,2-c] pyridine using astereoselective method, which involves as few steps as possible andproviding an appreciable yield of the desired compound remains ofincontestable importance.

It has been discovered rather surprisingly, according to the invention,that clopidogrel can be obtained in just 3 steps from(R)-2(2-chlorophenyl)-2-hydroxyacetic acid with a global yield of theorder of 80% by replacing themethyl-(R)-2(2-chlorophenyl)-2-halogenoacetate, bymethyl-(R)-2(2-chlorophenyl)-acetate, which has a sulphonyloxy group inthe 2 position, i.e. a compound with the above formula I.

This process is all the more surprising because:

A) the 2-methanesulphonyloxy groups and 2-toluenesulphonyloxy groups ofcarboxyl esters are known to undergo racemisation when they are involvedin a nucleophilic substitution by an amine function (Angew. Chem. Int.Ed. Eng. 22 (1983), no. 1 pp 65-66).

These claims have been confirmed in Tetrahedron, Vol. 47, no. 7, pp1109-1135 (1991), where it is reported that the 2-methanesulphonyloxyand 2-p-toluenesulphonyloxy esters of carboxylic acids are inappropriatesubstrates for a stereoselective nucleophilic substitution reaction inthe 2 position.

Similar observations have been published in Leibigs. Ann. Chem. 1986, p.314-433, where yields of <30% are reported as being obtained during thesubstitution of methyl-2-p-toluenesulphonyloxy- ormethyl-2-methanesulphonyloxy-propionate with benzylamine.

B) The (R) and (S) enantiomers of 2-sulphonyloxyacetic esters, whichinclude an additional 2-phenyl group, are known to produce compoundswith considerably reduced stereoselectivity after nucleophilicsubstitution in the 2-position.

For example, Tetrahedron, Vol. 44, no. 17, pp 5583-5595 (1988) reportsthe substitution of derivatives of (S) or (R)methyl-2-triflyloxy-2-X-acetate by O-benzylhydroxylamine indichloromethane as a solvent and at a temperature between 0° C. and roomtemperature in order to form the (R) and (S) acetic esters of2-O-benzylhydroxylamino-2-X respectively. As is known, the triflyl groupdesignates the trifluoromethylsulphonyl radical.

This reaction is found to be highly selective in the case of esters inwhich X represents an alkyl group, which may be substituted, such asmethyl or benzyl (enantiomeric excess, ee≧95%), but has much lowerselectivity when X represents the phenyl group since the enantiomericexcess of the corresponding (R)-2-O-benzylhydroxylamino-2-phenyl esteris no more than 50%. Very similar results have been reported after otherexperiments carried out using 2-sulphonyloxy derivatives of2-phenylacetic esters.

Thus:

a) Tetrahedron Letters, Vol. 31, no. 21, pp 2953-2956 (1990) describesthe substitution reaction of the methyl (S)-2-triflyloxy-2-X-acetateesters with t-butyloxycarbonylhydrazine or BOC-hydrazine, indichloromethane and at 0° C., to form (R)-2-BOC-hydrazinyl-2-X-aceticesters.

The selectivity of this reaction has also been shown to be veryconsiderable when X represents an alkyl group, which may be substituted,such as methyl, isobutyl or benzyl (ee>95%), but in contrast, verylimited when X represents phenyl (ee: 28%).

b) Tetrahedron, Vol. 48, no. 15, pp 3007-3020 (1992) reports thesubstitution of methyl (S)-2-nosyloxy-2-X-acetate derivatives with anazido group, the reaction taking place in dichloromethane and at roomtemperature, in order to form (R)-2-azido-2-X acetic esters.

Once more, the substitution of the 2-sulphonyloxy group, in this casethe nosyloxy group, takes place in a highly selective manner when Xrepresents an alkyl group, which may be substituted, such as methyl,isopropyl, sec-butyl or benzyl (ee>92%), but disappointing when Xrepresents the phenyl group (ee: 35%).

These latter findings actually led the authors of the publication inquestion to conclude that “the phenyl group is well known for reducingstereoselectivity when the esters of 2-nosyloxy and 2-triflyloxy estersare substituted by different classes of nucleophilic agents”. As isknown, the nosyl group designates the p-nitrophenylsulphonyl radical.

The sulphonyloxy derivatives of formula-I acetic esters that have shownthemselves to be particularly interesting synthesis intermediates,notably for the preparation of clopidogrel are:

-   methyl (R)-2-benzenesulphonyloxy-2(2-chlorophenyl) acetate-   methyl (R)-2(2-chlorophenyl)-2(p-toluenesulphonyloxy) acetate-   methyl (R)-2(2-chlorophenyl)-2-methanesulphonyloxy acetate-   methyl (R)-2(4-chlorobenzenesulphonyloxyl)-2-(2-chlorophenyl)    acetate-   methyl (R)-2(2-chlorophenyl)-2(2,4,6-trimethylbenzenesulphonyloxy)    acetate-   methyl    (R)-2(2-chlorophenyl)-2(2,4,6-triisopropylbenzenesulphonyloxy)    acetate-   methyl (R)-2(2-chlorophenyl)-2(4-nitrobenzenesulphonyloxy) acetate-   methyl (R)-2(2-chlorophenyl)-2(2,5-dichlorobenzenesulphonyloxy)    acetate

In particular, the following are preferred

-   methyl (R)-2-benzenesulphonyloxy-2(2-chlorophenyl) acetate-   methyl (R)-2(2-chlorophenyl)-2(2,4,6-trimethylbenzenesulphonyloxy)    acetate-   methyl    (R)-2(2-chlorophenyl)-2(2,4,6-triisopropylbenzenesulphonyloxy)    acetate-   methyl (R)-2(2-chlorophenyl)-2(4-nitrobenzenesulphonyloxy) acetate-   methyl (R)-2(4-chlorobenzenesulphonyloxyl)-2(2-chlorophenyl) acetate-   methyl (R)-2(2-chlorophenyl)-2(2,5-dichlorobenzenesulphonyloxy)    acetate.

The sulphonyloxy derivatives of the invention can be obtained byreacting the (R)-2(2-chlorophenyl)-2-hydroxy acetic ester with theformula:

with a sulphonyl anhydride or halogenide, with the general formulaR₁—SO₂—R₂  III

in which R₂ represents an OSO₂—R₁ group or, preferably, a halogen atomsuch as chlorine or bromine, and R₁ has the same significance as before,in the presence of a lithium salt and an aromatic amine which acts bothas a catalyst and acid acceptor such as pyridine, which yields thedesired compound.

The reaction in question is generally carried out in an aprotic solvent,such as a C₁-C₄ aliphatic hydrocarbide, preferably halogenated, forinstance dichloromethane, dichloroethane, chloroform, carbontetrachloride or tetrachloroethane, and at a temperature between 0° C.and room temperature.

In addition, the aromatic amine, preferably C₆-C₁₀, is used instoechiometric quantity or preferably a slight excess which can reach1.2 molar equivalent in terms of the formula-III compound.

The coupling reaction of the formula-I and formula-III compounds inwhich R₂ represents a halogen atom, can give rise to a side reactionwhich results in the formation of a halogenated derivative i.e. a methyl2(2-chlorophenyl)-2-halogenoacetate derivative.

However, it was fortuitously noticed that the presence of a lithium saltin the reaction mixture makes it possible to reduce this side reactionconsiderably and consequently to obtain high proportions of theformula-I compound.

By way of example, the reaction between methyl(R)-2(2-chlorophenyl)-2-hydroxyacetate with p-nitrobenzenesulphonylchloride or p-toluenesulphonyl chloride in dichloromethane at 20° C. andin the presence of pyridine and lithium perchlorate, produces a yield of92% of methyl (R)-2(2-chlorophenyl)-2(p-nitrobenzenesulphonyloxy)acetate and a yield of 85% of methyl(R)(2-chlorophenyl)-2(p-toluenesulphonyloxy) acetate respectively after5 hours, whereas the same reaction, conducted in the absence of lithiumperchlorate produces yields of only 28% and 30% of the end productrespectively.

This lithium salt, which can be for example, lithium perchlorate(LiClO₄) or lithium tetrafluoroborate (LiBF₄), is used in astoechiometric quantity. However, it is preferable to take a slightexcess of this lithium salt, that is up to 1.2 molar equivalent in termsof the formula-III compound.

As for the formula-II ester, it can be obtained using a non-racematingreaction by esterifying (R)-2(2-chlorophenyl)-2-hydroxyacetic acid or(R)-2-chloro-mandelic acid, which is a commercial product, with methanoland in the presence of a strong acid, such as sulphuric acid.

According to a variant of the above process, formula-I sulphonyloxyderivatives can also be prepared by reacting the formula-II ester with aformula-III halogenide in the presence of 4-dimethylaminopyridine ascatalyst and another acid acceptor, such as an aliphatic amine, forexample triethylamine to produce the desired compound.

The reaction is generally conducted at a temperature of −10° C. to +10°C., preferably at 0° C., and in an aprotic solvent, such as one of thosealready mentioned, notably dichloromethane.

The processes described above make it possible to obtain formula-Isulphonyloxy derivatives with particularly good yields, usually of theorder of 90 to 98% and with quite remarkable enantiomeric excesses of>99%.

As previously indicated, the sulphonyloxy derivatives of the inventioncan be used notably for the preparation of clopidogrel.

In consequence, another object of the invention concerns the preparationof clopidogrel by a process in which 4,5,6,7-tetrahydrothieno [3,2-c]pyridine in the form of a base or salt with a formula-I sulphonyloxyderivative in the presence of a basic agent used alone or in aqueous,solution, which yields the desired compound.

The reaction medium used is usually a polar solvent, such as a C₂-C₅aliphatic ester, for example ethyl or isopropyl acetate, a C₁-C₄aliphatic alcohol, N,N-dimethylformamide, a C₄-C₆ cyclic ester or aC₂-C₆ aliphatic ester such as tetrahydrofuran or isopropyl ether, aC₂-C₈ aliphatic ketone, for example methylisobutylketone or, preferably,a non-polar solvent, such as a C₁-C₄ halogenated aliphatic hydrocarbon,for example dichloromethane, dichloroethane, chloroform, carbontetrachloride or tetrachloroethane or a C₆-C₁₀ aromatic hydrocarbon, forexample benzene, toluene or a xylene so that a two-phase system isformed if water is present in the reaction medium. In this latter case,if necessary, a phase-transfer catalyst can be used, such as aquaternary ammonium, a phosphonium salt or a crown ether.

Similarly, the basic agent can be a carbonate of an alkaline metal, suchas sodium or potassium carbonate, or a bicarbonate of an alkaline metal,for instance sodium or potassium bicarbonate, and the reaction can beconducted at a temperature ranging from ambient temperature to thereflux temperature of the medium used.

As for the 4,5,6,7-tetrahydrothieno [3,2-c] pyridine, a known compound,it is used in a stoechiometric quantity but usually and preferably in anexcess which can be as much as 2.5 molar equivalents in terms of theformula-I sulphonyloxy derivative.

By conducting this latter reaction in toluene, methylisobutylketone orisopropyl acetate at a temperature of 80° C. over about 4 hours, it ispossible to obtain clopidogrel with a chemical yield in excess of 95%and with an enantiomeric excess of between 80 and 88%.

Using dichloromethane as the solvent and at a temperature of 40° C.:

-   -   a) the percentage converted into clopidogrel can reach 94 to 95%        in 5 hours with an enantiomeric excess of 96%.    -   b) starting from methyl        (R)-2(4-chlorobenzenesulphonyloxy)-2(2-chlorophenyl) acetate,        the conversion into clopidogrel reaches 100% after 10 hours and        the enantiomeric excess is 96%.    -   c) starting from methyl        (R)-2(2-chlorophenyl)-2(4-nitrobenzenesulphonyloxy) acetate, the        conversion into clopidogrel reaches 100% after 30 minutes and        the enantiomeric excess is >98%.

Using an alternative pathway, clopidogrel can also be prepared fromsulphonyloxy derivatives of the invention and 2(thien-2-yl)ethylamine.

Consequently, the invention also applies to the preparation ofclopidogrel according to a process in which:

-   -   a) 2(thien-2-yl)ethylamine in the form of the base or salt is        reacted with a formula-I sulphonyloxy derivative in the presence        in a basic agent used alone or in aqueous solution, to form        methyl (+)-(S)-α(2(thien-2-yl)ethylamino)-α-(2-chlorophenyl)        acetate, which has the formula:    -   b) the thienylethylamine derivative thus formed is reacted with        an formylation agent and cyclised in the presence of an acid,        which yields the desired compound.

The formylation agent used in the above process can be:

-   -   either formic aldehyde or any compound generally known to        release it in a reactive form, such as for example its hydrate        or its polymerisation derivatives. These formylation agents can        be considered to be preferred in the context of the invention.    -   or compounds with the general formula:        R₃—CH₂—R₄  V        in which R₃ represents a halogen atom, a C₁-C₄ alkyloxy group, a        C₁-C₄ alkylthio group or an amino group and R₄ represents a        C₁-C₄ alkoxy group, a C₁-C₄ alkylthio group, a C₂-C₅,        alkoxycarbonyl or phenoxycarbonyl group    -   or heterocyclic compounds with the general formula:        in which Z represents O, NH, or S, such as s-trioxane.

The step involving the use of 2(thien-2-yl)ethylamine, a known compound,can be conducted under the same operating conditions as those describedpreviously for the use of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine

The formylation and cyclisation step can give rise to intermediatecompounds, such as a hydroxymethyleneamine or a heterocycle of thetrimethylenetriamine type, as reported in patent EP 0 466 569.

Consequently, the reactions with the formylation and cyclisation agentcan be carried out successively, possibly by isolating the intermediatecompounds in question, or conversely, they can take placesimultaneously.

When the reactions occur successively, the step involving theformylation agent can be carried out optionally in the presence of anether, a hydrocarbon solvent, such as benzene, toluene, xylene orpetroleum ether or of a halogenated solvent, such as methylene chlorideor dichloroethane.

The cyclisation is then carried out in a polar solvent, such as water,an alcohol, dimethylformamide or in a mixture of these solvents.

As the formylation agent, formic aldehyde is generally preferred andthis can be added to the reaction medium in the form of an aqueoussolution.

The acid can be an organic or inorganic acid, in general a strong acid,such as sulphuric acid, or a hydracid, such as hydrochloric acid, or asulphonic acid, such as methanesulphonic acid.

When the reactions are carried out simultaneously, the reaction mediumconsists of a polar solvent, such as water or an alcohol, and the acid,which can be inorganic or organic, is added to the medium, preferably instoechiometric quantity in terms of the formula-IV compound employed. Inthis case, this acid is a strong acid which can be simply added to themedium in the form of its salt with the formula-IV compound. An acidicsolvent such as formic acid or acetic acid can also be used, the formercombined with paraformaldehyde being particularly preferred.

Clopidogrel is obtained according to the invention, that is by using thevarious methods described above, can then be purified if necessary, by aconventional method using a recrystallisation process or bychromatographic procedures.

The following non-exhaustive examples illustrate the invention.

PREPARATION Methyl (R)-2-hydroxy-2(2-chlorophenyl) Acetate

A 1000-ml reactor fitted with a double jacket and a valve in the bottom,a mechanical stirrer, a thermometer and a condenser is loaded with 120 g(0.643 mole) of (R)-2-hydroxy-2(2-chlorophenyl) acetic acid, 480 ml ofmethanol and 4.8 g of 95% sulphuric acid. The solution obtained is thenheated under reflux for 2 hours and the excess methanol is theneliminated under reduced pressure. The oily residue is then taken up in650 ml of dichloromethane and 240 g of an aqueous solution of 10%potassium carbonate.

After decanting, the chlorinated phase is washed with 200 ml of waterand then concentrated under reduced pressure.

In this manner, 124.4 g of methyl (R)-2-hydroxy-2(2-chlorophenyl)acetate is obtained in the form of a colourless oil.

Yield: 94%

Optical purity by liquid chromatography of the chiral phase: >99%.

NMR (CDCl₃): 7.4-7.2 ppm (multiplet 4 aromatic protons)

-   -   5.57 ppm (singlet, 1 CH proton)    -   3.76 ppm (singlet, 3 OCH₃ protons)    -   3.59 ppm (wide singlet, 1 OH proton)

EXAMPLES 1 TO 7 Methyl (R)-2-benzenesulphonyloxy-2(2-chlorophenyl)Acetate (Example 1)

In a dry, 100-ml tricol round-bottomed flask, fitted with a magneticstirrer, a condenser and a thermometer and operating under an atmosphereof nitrogen, is taken 3.81 g (36 mmoles) of lithium perchlorate, 30mmoles of benzenesulphonyl chloride and 45 ml of dichloroethane.

To the solution obtained, is added 2.9 ml (36 mmoles) of pyridine. Thenon-uniform white reaction medium is then stirred for 15 minutes beforeadding 6.0 g of methyl (R)-2-hydroxy-2(2-chlorophenyl) acetate dissolvedin 15 ml of dichloroethane.

The milky reaction mixture obtained is stirred for 5 hours and thenpoured over a stirred mixture of 120 ml of 1N hydrochloric acid and 240ml of dichloromethane. After decanting, the chlorinated phase is washedwith 120 ml of water and then concentrated under reduced pressure. Thesulphonate thus formed takes the form of a colourless, viscous liquid.Purification on a silica column yields an analytically pure sample.In this manner, methyl (R)-2-benzenesulphonyloxy-2(2-chlorophenyt)acetate is obtained.

Yield: 90%

Optical purity: >99% [α]₅₈₉²⁵ : −53^(∘)(2%, methanol)

NMR (CDCl₃) 7.88 ppm (doublet of triplets, 2 aromatic protons)

-   -   7.63 to 7.55 ppm (multiplet, 1 aromatic proton)    -   7.50 to 7.38 ppm (multiplet, 3 aromatic protons)    -   7.33 to 7.17 ppm (multiplet, 3 aromatic protons)    -   6.30 ppm (singlet, 1 (CH) proton)    -   3.70 ppm (singlet, 1 (OCH₃) proton).

Following the same process as that described previously, the followingcompounds have been prepared:

(R)-2(2-chlorophenyl)-2(4-p-toluenesulphonyloxy) Acetate (Example 2)

Yield: 85%

Optical purity: >99% [α]₅₈₉²⁵ : −58.3^(∘)(2%, methanol)

NMR (CDCl₃) 7.75 to 7.25 ppm (multiplets, 8 aromatic protons)

-   -   5.79 ppm (singlet, 1 (CH—O) proton)    -   3.67 ppm (singlet, 3 (OCH₃) protons)    -   2.41 ppm (singlet, 3 (CH₃-phenyl) protons)

Methyl (R)-2(2-chlorophenyl)-2-methanesulphonyloxy Acetate (Example 3)

Yield: 87%

Optical purity: >99% [α]₅₈₉²⁵ : −75.6^(∘)(2%, methanol)

NMR (CDCl₃) 7.49 to 7.28 ppm (multiplets, 4 aromatic protons)

-   -   6.40 ppm (singlet, 1 (CH) proton)    -   3.79 ppm (singlet, 3 (OCH₃) protons)    -   3.14 ppm (singlet, 3 (SO₂CH₃) protons)

Methyl (R)-2(4-chlorobenzenesulphonyloxy)-2(2-chlorophenyl) Acetate(Example 4)

Yield: 90%

Optical purity: >99%

NMR (CDCl₃) 7.8 and 7.43 ppm (2 doublets, 4 aromatic protons)

-   -   7.42 to 7.18 ppm (multiplet, 4 aromatic protons)    -   6.31 ppm (singlet, 1 (CH) proton)    -   3.73 ppm (singlet, 3 (OCH₃) protons)

Methyl (R)-2(2-chlorophenyl)-2(2,4,6-trimethylbenzenesulphonyloxyAcetate (Example 5)

Yield: 93%

Optical purity: >99%

NMR (CDCl₃) 7.50 to 7.20 ppm (multiplet, 4 aromatic protons)

-   -   6.92 ppm (singlet, 2 aromatic protons)    -   6.21 ppm (singlet, 1 (CH) proton)    -   3.69 ppm (singlet, 3 (OCH₃) protons)    -   2.62 ppm (singlet, 6 (CH₃) protons)    -   2.30 ppm (singlet, 3 (CH₃) protons)

Methyl (R)-2(2-chlorophenyl)-2(2,4,6-triisopropylbenzenesulphonyloxy)Acetate (Example 6)

Yield: 93%

Optical purity: >99%

NMR (CDCl₃) 7.50 to 7.20 ppm (multiplet, 4 aromatic protons)

-   -   7.14 ppm (singlet, 2 aromatic protons)    -   6.25 ppm (singlet, 1 (CH) proton)    -   4.09 ppm (septuplet, 2 (2CH-isopropyl) protons)    -   3.71 ppm (singlet, 3 (OCH₃) protons)    -   2.85 ppm (septuplet, 1 (CH isopropyl) proton)    -   1.24 ppm (doublet, 6 (2 CH₃) protons)    -   1.22 ppm (doublet, 6 (2 CH₃) protons)    -   1.10 ppm (doublet, 6 (2 CH₃) protons)

Methyl (R)-2(2-chlorophenyl)-2(4-nitrobenzenesulphonyloxy) Acetate(Example 7)

Yield: 92%

Optical purity: >99%

NMR (CDCl₃) 8.29 and 8.06 ppm (2 doublets, 4 aromatic protons)

-   -   7.40 to 7.15 ppm (multiplet, 4 aromatic protons)    -   6.37 ppm (singlet, 1 (CH) proton)    -   3.74 ppm (singlet, 3 (OCH₃) protons)

Example 8 Methyl (R)-2-benzenesulphonyloxy-2(2-chlorophenyl) Acetate

In a dry, tricol round-bottomed flask, fitted with a double-jacket, amagnetic stirrer, a condenser and a thermometer and operating under anatmosphere of nitrogen, is taken 0.72 g (6 mmoles) of4-dimethylaminopyridine, 12.0 g (60 mmoles) of methyl(R)-2-hydroxy-2(2-chlorophenyl) acetate, 6.06 g (60 mmoles) oftriethylamine and then 20 ml of dichloromethane. The colourless solutionobtained is cooled to 0° C. and then, operating at this temperature, 60mmoles of benzenesulphonyl chloride in solution in 30 ml ofdichloromethane is added. The reaction mixture is stirred for 3 hours at0° C. and then tipped onto a stirred mixture consisting of 240 ml of 1Nhydrochloric acid and 240 ml of dichloromethane.

After decanting, the chlorinated phase is washed with 120 ml of waterand then concentrated under reduced pressure.

The sulphonate thus formed takes the form of a colourless viscousliquid. An analytically pure sample is obtained after purifying on asilica column.

In this manner, methyl (R)-2-benzenesulphonyloxy-2(2-chlorophenyl)acetate is obtained:

Yield: 97%

Optical purity: >99% [α]₅₈₉²⁵ : −53^(∘)(2%, methanol)

Following the same process as that described above, the followingcompounds are obtained:

Methyl (R)-2(2-chlorophenyl)-2(4-nitrobenzenesulphonyloxy) Acetate(Example 9)

Yield: 88%

Optical purity: >99%

Methyl (R)-2(2-chlorophenyl)-2(2,5-dichlorobenzenesulphonyloxy) Acetate(Example 10)

Yield: 95%

Optical purity: >99%

NMR (CDCl₃) 7.98 ppm (doublet, 1 aromatic proton)

-   -   7.15 to 7.50 ppm (multiplets, 6 aromatic protons)    -   6.38 ppm (singlet, 1 (CH) proton)    -   3.74 ppm (singlet, 3 (OCH₃) protons)

Example 11 Methyl (R)-2-benzenesulphonyloxy-2(2-chlorophenyl) Acetate

This compound was obtained using the method described in Example 8, butreplacing the dichloromethane by toluene.

Yield: 95%

Example 12 Methyl (R)-2-benzenesulphonyloxy-2(2-chlorophenyl) Acetate

In a dry, tricol round-bottomed flask, fitted as in Example 8 is taken0.72 g (6 mmoles; 0.1 equivalent) of 4-dimethylaminopyridine, 12.0 g (60mmoles; 1 equivalent) of methyl (R)-2-hydroxy-2(2-chlorophenyl) acetateand 7.8 g (78 mmoles; 1.3 equivalent) of triethylamine and 20 ml ofdichloromethane. The colourless solution obtained is cooled to 0° C. andthen, operating at this temperature, 6.06 g (60 mmoles; 1 equivalent) ofbenzenesulphonyl chloride in solution in 30 ml of dichloromethane. Thereaction mixture is stirred for 3 hours at 0° C. and then tipped onto astirred mixture consisting of 240 ml of 1N hydrochloric acid and 240 mlof dichloromethane, while stirring this mixture.

After decanting, the chlorinated phase is washed with dilutehydrochloric acid and then with water, before being concentrated underreduced pressure. An analytically pure sample is obtained afterpurifying on a silica column.

In this manner, methyl (R)-2-benzenesulphonyloxy-2(2-chlorophenyl)acetate is obtained:

Yield: 98%

Optical purity: 100%, (S(+) enantiomer not detected).

Example 13 Methyl (S)-2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl) Acetate

In a dry, 50-ml tricol round-bottomed flask, fitted with a doublejacket, a magnetic stirrer, a condenser and a thermometer, is taken Ymmoles of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine in solution in 7.5ml of solvent and 2.85 g of a 30% aqueous solution of potassiumcarbonate. After stirring for 10 minutes, 5 mmoles of the formula-Icompound, previously dissolved in 2.5 ml of solvent, is added.

The two-phase medium thus obtained is heated under reflux for the timeindicated and then cooled to 70° C. and decanted.

In this manner, methyl (S)-2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl) acetate or clopidogrel is obtained

NMR (CDCl₃) 7.70 ppm (multiplet, 1 aromatic proton of benzene)

-   -   7.41 ppm (multiplet, 1 aromatic proton of benzene)    -   7.33 to 7.22 ppm (multiplet, 2 aromatic protons of benzene)    -   7.06 ppm (doublet, 1 aromatic proton of thiophene)    -   6.67 ppm (doublet, 1 aromatic proton of thiophene)    -   4.93 ppm (singlet, 1 CHCO proton)    -   3.73 ppm (singlet, 3 OCH₃ protons)    -   3.76 and 3.64 ppm (2 doublets, 2 CH₃ protons)    -   2.89 ppm (singlet, 4 2CH₂ protons)

Depending on the formula-I compounds used, the concentrations of4,5,6,7-tetrahydrothieno [3,2-c] pyridine used, the yields obtainedusing the above solvents and reaction times are as follows:

Clopidogrel Formula-I Reaction Optical compound Y time purity R1(mmoles) Solvent (h) Yield (%) (%) Phenyl 5 toluene 4.5 85 90 (1.7 g; 1equivalent) Phenyl 6 dichloro- 5 94.5 96.2 (1.2 equivalent) methanePhenyl  12.5 dichloro- 5 98.5 89 (2.5 equivalent) methane 4-chloro- 6dichloro- 10 about 100 96 phenyl methane 4-nitro- 6 dichloro- 0.5 about100 >98 phenyl methane

Example 14

Methyl (S)-2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl) Acetate

In a 50-ml tricol round-bottomed flask, fitted with a double-jacket, amagnetic stirrer, a condenser and a thermometer is taken 1.2 mmoles of4,5,6,7-tetrahydrothieno [3,2-c] pyridine in solution in 7.5 ml ofdichloromethane and 2.85 g of a 30% aqueous solution of potassiumcarbonate. After stirring for 10 minutes, 5 mmoles of methyl(R)-2(2-chlorophenyl)-2(2,5-dichlorobenzenesulphonyloxy) acetate,previously dissolved in 2.5 ml of solvent is added.

The two-phase medium thus obtained is heated under reflux for 3.5 hours,cooled to 70° C. and then decanted.

In this manner, methyl (S)-2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl) acetate is obtained.

Yield: 89%

Optical purity: 96%

Example 15 Methyl (S)-2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl) Hemisulphate or Clopidogrel Hemisulphate

a) Methyl (+)-(S)-α-(2-thien-2-yl) ethylamino)-α-(2-chlorophenyl)Acetate

In a 250-ml reactor, fitted with a double jacket, a motor-drivenstirrer, a condenser and a thermometer is taken 7.62 g of 2(thien-2-yl)ethylamine (0.06 mole; 1.2 molar equivalent in terms of the sulphonyloxyderivative) in solution in 67.5 ml of dichloromethane and an aqueoussolution of 7.0 g of potassium bicarbonate (0.07 mole; 1.4 equivalent interms of the sulphonyloxy derivative) in 30 ml of water. After stirringfor 5 minutes, 0.05 mole (1 equivalent) of the formula-I compound isadded, dissolved in 40 ml dichloromethane.

The two-phase medium thus obtained is heated under reflux for the timeindicated, cooled and then decanted and the (+) methyl(S)-α(2-thien-2-yl)ethylamino-α(2-chlorophenyl) acetate (formula IV) iscollected.

Depending on the formula-I compounds used and with the above reactiontimes, the following yields are obtained:

Formula-I compound Reaction Formula IV-compound R1 time (h) Yield (%)Optical purity (%) methyl 29 65 76 phenyl 22 71 92 4-chlorophenyl 11 9492 4-nitrophenyl   2 99 95 2,5-dichlorophenyl   6 98 97

b) Clopidogrel Hemisulphate

While stirring, 20.5 g of (+) methyl(S)-α(2-thien-2-yl)ethylamino-α(2-chlorophenyl) acetate in solution in200 ml of methylene chloride is added over 25 minutes to 40 ml of 30%(w/w) of an aqueous solution of formic aldehyde.

After stirring for 3 hours, the organic phase is decanted, washed withwater, dried and the solvent evaporated. The residue is dissolved in 50ml of methylene chloride and the solution, at a temperature of 60° C.,is added to 100 ml of anhydrous N,N-dimethylformamide containing 6Nhydrochloric acid. After one hour and a half, the solvents areeliminated by distilling under reduced pressure and the residue isdissolved in 200 ml of methylene chloride and 100 ml water.

Sodium bicarbonate is added to release the base from its hydrochloride,the organic phase decanted, dried and concentrated under reducedpressure, which yields clopidogrel in the form of the free base.

The hemisulphate of this basic compound is then formed in 150 ml ofacetone by reacting with 4.9 g of concentrated sulphuric acid (96%).

In this manner, 17 g of clopidogrel hemisulphate is obtained.[α]_(D)²⁰ = 53^(∘)(C = 1, methanol)

1. A compound of the formula:

in which R1 represents a benzyl group, a C₁-C₄ alkyl, which may besubstituted by one or several halogen atoms or a phenyl group, which maybe substituted by one or several halogen atoms or by one or severallinear or branched C₁-C₄ alkyl groups or by a nitro group.
 2. A compoundaccording to claim 1, in which R₁ represents a methyl, ethyl, propyl,trifluoromethyl, benzyl, phenyl, chlorophenyl, dichlorophenyl, tolyl,trimethylphenyl, triisopropylphenyl, or nitrophenyl group. 3.Methyl(R)-2-benzenesulphonyloxy-2(2-chlorophenyl) acetate according toclaim
 2. 4.Methyl(R)-2(2-chlorophenyl)-2(2,4,6-trimethylbenzenesulphonyloxy)acetate according to claim
 2. 5.Methyl(R)-2(4-chlorobenzenesulphonyloxyl)-2(2-chlorophenyl) acetateaccording to claim
 2. 6.Methyl(R)-2(2-chlorophenyl)-2(4-nitrobenzenesulphonyloxy) acetateaccording to claim
 2. 7.Methyl(R)-2(2-chlorophenyl)-2(2,4,6-triisopropylbenzene-sulphonyloxy)acetate according to claim
 2. 8.Methyl(R)-2(2-chlorophenyl)-2(2,5-dichlorobenzenesulphonyloxy) acetateaccording to claim
 2. 9. A process for the preparation of a compoundaccording to claim 1 which comprises reacting a(R)-2(2-chlorophenyl)-2-hydroxy acetic ester of the formula:

with a sulphonyl anhydride or halogenide with the formula:R₁—SO₂—R₂  III in which R₂ represents an OSO₂—R₁ group or a halogen atomand R₁ has the same significance as in claim 1, the reaction takingplace in the presence of a lithium salt and an aromatic amine to formthe desired compound of formula I.
 10. A process according to claim 9wherein the lithium salt used is lithium perchlorate or lithiumtetrafluoroborate.
 11. A process according to claim 9 wherein thelithium salt is used in a quantity of 1 or 1.2 molar equivalent permolar equivalent of the formula III-compound.
 12. A process according toclaim 9 wherein the aromatic amine used is pyridine or4-dimethylaminopyridine.
 13. A process according to claim 12 wherein thearomatic amine is used in a quantity of 1 to 1.2 molar equivalent permolar equivalent of the formula-III compound.
 14. A process according toclaim 9 wherein the reaction takes place at a temperature of between 0°C. and room temperature.
 15. A process for the preparation of a compoundaccording to claim 1 which comprises reacting a(R)-2(2-chlorophenyl)-2-hydroxy acetic ester of the formula:

with a sulphonyl anhydride or halogenide, with the formulaR₁—SO₂—R₂  III in which R₂ represents an OSO₂—R₁ group or a halogen atomand R₁ has the same significance as in claim 1, the reaction takingplace in the presence of 4-dimethylaminopyridine and another acidacceptor, to yield the desired compound of Formula I.
 16. A processaccording to claim 15 wherein the acid acceptor is an amine.
 17. Aprocess according to claim 15 wherein the reaction takes place at atemperature of between −10° C. and +10° C.
 18. A process according toclaim 9 wherein the reaction takes place in an aprotic solvent.
 19. Aprocess according to claim 18 wherein the aprotic solvent is ahalogenated hydrocarbon.
 20. A process according to claim 15 wherein thereaction takes place in an aprotic solvent.
 21. A process according toclaim 20 wherein the aprotic solvent is a halogenated hydrocarbon.